Studies toward the total synthesis of carolacton

Article abstract of DOI:10.1055/s-0032-1317700

An efficient synthesis of the C1-C19 segment of carolacton is described, starting from d-ribose, (-)-β-citronellene and a homopropargylic alcohol, and which employs a Nozaki-Hiyama-Kishi (NHK) coupling as the key step. Other important steps are cross-metathesis and Evans aldol reactions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317700

PAPER
▌251
paper
Studies toward the Total Synthesis of Carolacton
Studies toward the Total Synthesis of Carolacton
Gowravaram Sabitha,* K. Shankaraiah, M. Nagendra Prasad, Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received: 26.09.2012; Accepted after revision: 07.11.2012
have been studying the total synthesis of this natural prod-
uct. The first total synthesis of carolacton (1) was reported
by Schmidt and Kirschning.7 Herein, we report our prog-
ress on the stereoselective synthesis of the C1–C19 seg-
ment of 1 using a Nozaki–Hiyama–Kishi (NHK) coupling
as the key step.
Abstract: An efficient synthesis of the C1–C19 segment of carolac-
ton is described, starting from D-ribose, (–)-β-citronellene and a ho-
mopropargylic alcohol, and which employs a Nozaki–Hiyama–
Kishi (NHK) coupling as the key step. Other important steps are
cross-metathesis and Evans aldol reactions.
Key words: carolacton, macrolide, Evans aldol, Nozaki–Hiyama–
Kishi coupling, cross-metathesis
OH
OH
Carolacton (1) (Figure 1), a macrolide ketocarbonic acid,
was isolated from a myxobacterium of the species Soran-
gium cellulosum, strain So ce960.1 Carolacton showed
high antimicrobial activity against biofilms of Streptococ-
cus mutans.2 Bacterial biofilms impose severe health
threats as they are able to grow on natural tissues or on
medical devices such as stents, bone implants and artifi-
cial valves.3 Furthermore, dental caries, gingivitis and
periodontal diseases, being the most common bacterial in-
fections in humans, and which may develop as a conse-
quence of dental plaque formation, are also caused by
bacterial biofilms.4 The antibiotic resistance of bacteria in
biofilms is high and hence their eradication has become
more difficult. Carolacton (1) showed a minimum inhibi-
tory concentration (MIC) value of 0.06 μg/mL against E.
coli, strain tolC. In addition, minor antifungal activity5
was observed against Aspergillus niger, Pythium debary-
anum and Sclerotinia sclerotiorum in the range of 16–20
μg/mL. The carbon skeleton of carolacton (1) was protect-
ed by a Japanese Patent, as a minor analog of the antifun-
gal agent YA2-M, in 2002.6 Carolacton was found to
reduce the number of viable cells in biofilms at nanomolar
concentrations, and is a highly potent agent against bio-
films containing the caries and endocarditis-associated
bacterium, Streptococcus mutans. The reported data
shows that in biofilms, carolacton causes membrane dam-
age and cell death, as well as morphological changes, for
example, elongated cells, increased chain length and bulg-
ing.2 The structure of 1 was elucidated by HRMS, IR and
2D NMR spectroscopy. The configurations of the stereo-
genic centers were determined by chemical derivatization,
molecular modeling and finally verified by X-ray crystal
structure analysis. The promising biological activity of
carolacton has made it a potential candidate for antimicro-
bial therapy. Inspired by the pronounced activity of 1, and
to provide material for further biological evaluation, we
O
O
O
OMe
O
OH
carolacton (1)
Figure 1 Structure of carolacton (1)
The retrosynthesis of carolacton (1) is shown in Scheme
1. Macrolide 1 can be synthesized by Yamaguchi macro-
lactonization of key segment 2, which can itself be pre-
pared via Nozaki–Hiyama–Kishi (NHK) coupling
between the C9–C19 aldehyde 3 and the C1–C8 iodo-
alkene 4. The fragment 3 could be obtained by a cross-
metathesis (CM) reaction between fragments 5 and 6. The
fragment 5 could in turn be prepared from D-ribose (7),
whereas the fragment 6 could be prepared from (–)-β-cit-
ronellene (8). The iodoalkene fragment 4 can be generated
starting from p-methoxybenzyl (PMB) protected homo-
propargylic alcohol 9.
The synthesis of the C1–C8 iodoalkene fragment 4 began
from the known p-methoxybenzyl ether 98 (Scheme 2).
Epoxy alcohol 10 was prepared from 9 as previously
reported8 in 95% ee. Epoxide-opening proceeded smooth-
ly and with high regioselectivity by treatment of the epoxy
alcohol 10 with lithium dimethylcuprate (Me2CuLi) to
give the corresponding 1,3-diol 11 accompanied by a mi-
nor amount of the undesired 1,2-diol (ratio 6:1). The mi-
nor isomer was readily removed by treating the mixture
with sodium periodate to give the pure 1,3-diol 11 in 75%
yield, possessing anti stereochemistry at the two stereo-
centers.9 After protection of the primary alcohol to give
tert-butyldimethylsilyl ether 12, O-methylation of the sec-
ondary hydroxy group using sodium hydride and methyl
iodide provided methyl ether 13 in 95% yield. Next, the
tert-butyldimethylsilyl group was removed and the result-
ing alcohol 14 was oxidized to give the corresponding al-
dehyde. This aldehyde was subjected to the Evans aldol
reaction with the boron enolate of chiral (S)-4-benzyl-3-
SYNTHESIS 2013, 45, 0251–0259
Advanced online publication: 17.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317700; Art ID: SS-2012-Z0757-OP
© Georg Thieme Verlag Stuttgart · New York

252
G. Sabitha et al.
PAPER
carolacton (1)
O
OTBS OMe
OH
O
O
1
OPMB
19
MeO
2
NHK coupling
O
OTBS OMe
O
O
1
8
I
CHO
+
OPMB
9
MeO 19
3
4
CM
Evans aldol
PMBO
reaction
O
O
O
OH
+
MeO
9
5
6
O
OH
HO
HO
OH
8
7
Scheme 1 Retrosynthetic analysis of carolacton (1)
propionyloxazolidin-2-one to give, exclusively, the syn
selective aldol adduct 15 (20:1 dr) in 87% yield.10 After
protection of the secondary hydroxy group in 15 to afford
tert-butyldimethylsilyl ether 16 (TBSOTf and 2,6-lutidine
in dichloromethane), subsequent removal of the chiral
auxiliary with lithium borohydride (LiBH4) in methanol
furnished the desired primary alcohol 17 in good yield.
This alcohol was oxidized using Dess–Martin periodinane
and the resulting aldehyde was transformed into alkyne 19
via dibromoalkene 18, according to the Corey–Fuchs pro-
tocol.11 Thus treatment of 18 with n-butyllithium (2.5
equiv) followed by in situ addition of methyl iodide to the
reaction mixture gave directly alkyne 19 in 94% yield.
Next, regioselective hydrozirconation of compound 19
with Schwartz’s reagent (HZrCp2Cl)12 was studied. Reac-
tion of alkyne 19 with Schwartz’s reagent, generated in
situ by the slow addition of diisobutylaluminum hydride
(1 equiv) to bis(cyclopentadienyl)zirconium(IV) dichlo-
ride (ZrCp2Cl2) in tetrahydrofuran, followed by quench-
ing with iodine gave iodooalkene 4 (the C1–C8 segment
of carolacton) in 88% yield.
O
a, b
ref. 8
PMBO
PMBO
OH
9
10
OH
OMe
e
d
OR
OTBS
O
PMBO
c
PMBO
PMBO
13
11 R=H
12
R=TBS
O
OMe OR
OMe
f, g
N
O
OH
PMBO
R=H
15
14
h
Ph
R=TBS
16
OMe OTBS
j, k
i
OH
l
PMBO
17
OMe OTBS
Br
PMBO
Br
m
18
OMe OTBS
Our approach to the synthesis of the cross-metathesis
(CM) coupling fragment 6 began from inexpensive and
commercially available (–)-β-citronellene (8), and is
shown in Scheme 3. Accordingly, compound 8 was epox-
idized with m-chloroperoxybenzoic acid to afford the 6,7-
epoxy derivative of citronellene 20, which was converted
into the corresponding aldehyde by subjecting it to selec-
tive oxidative cleavage with periodic acid (H5IO6) in tet-
rahydrofuran.13 This was subjected to homologation via a
two-carbon Wittig olefination to afford α,β-unsaturated
ester 21 (E-isomer) as the sole product (73% yield over
two steps).
OMe OTBS
I
PMBO
PMBO
4
19
Scheme 2 Synthesis of key intermediate 4. Reagents and conditions:
(a) Me2CuLi, Et2O, –40 °C, 3.5 h; (b) NaIO4, THF–H2O (4:1), 0 °C–
r.t., 80% (over 2 steps); (c) TBDMSCl, imidazole, anhyd CH2Cl2, 1 h,
0 °C, 92%; (d) NaH, MeI, 0 °C, 2 h, 95%; (e) TBAF, THF, 0 °C, 2 h,
85%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C to 0 °C, 3 h, 92%;
(g) (S)-4-benzyl-3-propionyloxazolidin-2-one, Bu2BOTf, Et3N,
CH2Cl2, –78 °C, 87%; (h) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 4 h,
98%; (i) LiBH4, THF, MeOH, 0 °C, 1 h, 90%; (j) Dess–Martin per-
iodinane, NaHCO3, CH2Cl2, 0 °C, 1.5 h, 85%; (k) Ph3P, CBr4, Et3N,
CH2Cl2, –10 °C, 3.5 h, 93%; (l) n-BuLi, MeI, THF, –78 °C to –25 °C,
94%; (m) ZrCp2Cl2, DIBAL-H, I2, THF, 0 °C, 3 h, 88%.
Subsequent reduction of the internal double bond with
magnesium in methanol14 gave the saturated ester 22 in
Synthesis 2013, 45, 251–259
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Studies toward the Total Synthesis of Carolacton
253
With practical routes to coupling partners 5 and 6 estab-
lished, we turned our attention to the key cross-metathesis
in the presence of Grubbs’ second generation catalyst18
(Scheme 5). Thus, the cross-metathesis reaction between
alkenes 5 and 6 gave the coupled product 27 in 75% yield.
The formation of homo-products was also observed if the
reaction was prolonged beyond 10 hours at room temper-
ature, or was performed at reflux temperature. The prima-
ry alcohol in compound 27 was then oxidized using Dess–
Martin periodinane to give aldehyde 3 in 85% yield.
O
b
a
20
8
c
OMe
d
OEt
22
O
O
O
21
Ph
OH
O
e
f
N
O
O
23
24
Ph
O
O
OH
OH
+
MeO
g
O
OH
N
O
6
5
6
O
O
25
Scheme 3 Synthesis of key intermediate 6. Reagents and conditions:
(a) MCPBA, CH2Cl2, NaOAc, –20 °C, 1 h, 85%; (b) (i) H5IO6, THF–
H2O (5:1), 0 °C; (ii) Ph3P=CHCO2Et, CH2Cl2, r.t., 0.5 h, 73% (over 2
steps); (c) Mg, anhyd MeOH, 0 °C, 1 h, 90%; (d) LiOH·H2O, THF–
MeOH–H2O (4:1:1), 0 °C, 2 h, 85%; (e) Et3N, PivCl, (S)-4-benzylox-
azolidin-2-one, LiCl, THF, –20 to 0 °C, 2 h, 95%; (f) NaHMDS, MeI,
THF, –78 °C, 3 h, 92%; (g) LiBH4, THF, MeOH, 0 °C, 1 h, 90%.
O
a
O
MeO
MeO
O
27
O
b
O
CHO
O
3
90% yield, which was then hydrolyzed under basic condi-
tions to furnish the corresponding carboxylic acid 23 in
85% yield. Coupling of acid 23 with the Evans chiral ox-
azolidinone [(S)-4-benzyloxazolidin-2-one], using piv-
aloyl chloride (PivCl) in presence of triethylamine and
lithium chloride furnished the required product 24 in 95%
yield.15 Diastereoselective methylation of the sodium eno-
late of compound 24 with methyl iodide furnished the de-
sired oxazolidinone 25 in 92% yield and in excellent
Scheme 5 Synthesis of key intermediate 3. Reagents and conditions:
(a) Grubbs II catalyst, CH2Cl2, r.t., 10 h, 75%; (b) Dess–Martin per-
iodinane, NaHCO3, CH2Cl2, 0 °C, 1.5 h, 85%.
Having successfully synthesized the two key intermedi-
ates, aldehyde 3 and iodoalkene 4, the next task was the
Nozaki–Hiyama–Kishi19 coupling reaction to give the
C1–C19 fragment 2. To optimize the Nozaki–Hiyama–
Kishi reaction between aldehyde 3 (1 equiv) and iodo-
alkene 4 (3 equiv) using chromium(II) chloride (CrCl2)
and nickel(II) chloride (NiCl2), screening of several pa-
rameters: solvent, temperature, time and the concentration
of catalyst was performed. Initially, the reaction was per-
formed in different solvents (DMF, MeCN, THF, DMF–
THF, DMSO), at room temperature using chromium(II)
chloride (6 equiv) and nickel(II) chloride (0.1 equiv). Di-
methyl sulfoxide was found to be superior to the other sol-
vents tested. The coupling was also conducted with
different concentrations of the catalysts in dimethyl sulf-
oxide as the solvent. The use of chromium(II) chloride (10
equiv) and nickel(II) chloride (0.05 equiv) gave the C1–
C19 segment 2 as an epimeric mixture (1.5:1 dr),20 in a
yield of 31% (after 10 h), along with recovered starting
material 3. Prolonged reaction times did not increase the
yield. Whilst these screening studies on the asymmetric
Nozaki–Hiyama–Kishi21 reaction were in progress,
Kirschning et al.7 successfully utilized [1,3-bis(diphe-
nylphosphino)propane]nickel(II) chloride [NiCl2(dppp)]
and a chiral ligand in their version of this coupling reac-
tion.
1
diastereoselectivity (>97:3),16 as confirmed by H NMR
spectroscopy. Removal of the chiral auxiliary with lithium
borohydride in methanol and tetrahydrofuran gave the de-
sired primary alcohol 6 in 90% yield with a new stereo-
genic center installed at C-2.
The synthesis of fragment 5 began with the conversion of
the commercially available chiral building block, D-ribose
(7) into the known aldehyde 2617 (Scheme 4). Subsequent
oxidation using sodium chlorite and 2-methyl-2-butene in
tert-butyl alcohol under buffered conditions gave the ex-
pected carboxylic acid in 85% yield. This was converted
into the corresponding methyl ester using diazomethane
to afford ester 5 in 95% yield.
O
OH
O
O
ref. 17
a, b
O
HO
O
OMe
CHO
HO
OH
O
7
5
26
Scheme 4 Synthesis of key intermediate 5. Reagents and conditions:
(a) NaHPO4, NaClO2, 2-methyl-2-butene, t-BuOH, 0 °C, 1.5 h, 85%;
(b) CH2N2, Et2O, –10 °C, 1 h, 95%.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 251–259

254
G. Sabitha et al.
PAPER
O
O
OTBS OMe
O
I
CHO
OPMB
+
MeO
3
4
OH
O
OH
O
O
OTBS OMe
OH
O
O
O
OMe O
a
OPMB
MeO
OH
2
carolacton (1)
Scheme 6 Synthesis of the C1–C19 segment 2 of carolacton. Reagents and conditions: (a) CrCl2, NiCl2, DMSO, r.t., 10 h, 31% (as a 6:4 mix-
ture of epimers).
by cleaving the 1,2-diol). This mixture of diols was dissolved in
THF (200 mL) and treated with NaIO4 (4.22 g, 19.7 mmol) in H2O
(50 mL) for 1 h to cleave the 1,2-diol. The aq layer was extracted
with Et2O (3 × 100 mL), and the combined extracts dried over
Na2SO4, concentrated in vacuo, and the residue subjected to silica
gel column chromatography (Rf = 0.35, EtOAc–hexane, 4:6) to af-
ford diol 11 (7.52 g, 74%) as a pale-yellow liquid.
In conclusion, we have accomplished the synthesis of the
C1–C19 segment 2 of carolacton starting from relatively
cheap and commercially available D-ribose, a homo-
propargylic alcohol and (–)-β-citronellene utilizing cross-
metathesis, Evans aldol and Nozaki–Hiyama–Kishi reac-
tions as the key steps. Further efforts are ongoing in our
laboratory to complete the total synthesis of carolacton
(1).
[α]D27 +8.0 (c 0.5, CHCl3).
IR (KBr): 3389, 2957, 2874, 1454, 1094, 1026, 740 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 9.0 Hz, 2 H), 6.84 (d,
J = 9.0 Hz, 2 H), 4.40 (s, 2 H), 4.29 (br s, 1 H), 3.80 (s, 3 H), 3.77-
3.53 (m, 5 H), 1.83–1.75 (m, 2 H), 1.74–1.63 (m, 1 H), 0.85 (d, J =
6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 129.6, 129.2, 113.7, 76.7,
72.9, 68.7, 67.2, 55.0, 39.9, 34.1, 13.6.
MS (ESI): m/z = 277 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H22O4Na: 277.1415;
All reactions were carried out under an inert Ar or N2 atmosphere
using standard syringe, septa, and cannula techniques, unless other-
wise mentioned. Commercial reagents were used without further
purification. All solvents were purified by standard techniques. Col-
umn chromatography was performed using Merck silica gel (60–
120 mesh) and the column was usually eluted with EtOAc–hexane.
TLC was carried out using Merck silica gel plates. Visualization of
the spots on the TLC plates was achieved by exposure to iodine va-
por or UV light, or by dipping the plates into H2SO4–β-naphthol,
ethanolic anisaldehyde–H2SO4–AcOH or H2SO4–phosphomolyb-
dic acid solutions, and heating the plates at 120 °C. Optical rotations
were obtained using a Perkin–Elmer 241 polarimeter in 1.0 dm (1.0
mL) cells. Infrared (IR) spectra were recorded with a Perkin–Elmer
683 spectrometer with NaCl optics. Spectra were calibrated against
the polystyrene absorption at 1610 cm–1. Samples were scanned
found: 277.1427.
(2S,3R)-1-[(tert-Butyldimethylsilyl)oxy]-5-[(4-methoxyben-
zyl)oxy]-2-methylpentan-3-ol (12)
To a stirred soln of the diol 11 (7.4 g, 29.13 mmol) in anhyd CH2Cl2
(60 mL), imidazole (3.96 g, 58.26 mmol) was added at 0 °C. After
15 min, TBDMSCl (4.39 g, 29.13 mmol) was added to the mixture
at 0 °C and stirring was continued for 1 h. After completion of the
reaction as indicated by TLC, the mixture was concentrated under
reduced pressure and the residue purified by column chromatogra-
phy (Rf = 0.48, EtOAc–hexane, 1:9) to yield the product 12 (9.86 g,
92%) as a colorless liquid.
1
neat, as KBr wafers or as a thin films in CHCl3. H NMR spectra
were recorded in CDCl3 using a Bruker 300 or Varian Unity 500
spectrometer. 13C NMR spectra were recorded at 75 MHz in CDCl3
using tetramethylsilane as the reference standard. Mass spectra
were recorded on Finnigan MAT1020B or Micromass VG 70-70H
spectrometers, operating at 70 eV using a direct inlet system. High-
resolution mass spectra (HRMS; ESI+) were obtained using a TOF
or a double focusing spectrometer.
[α]D27 +11 (c 0.5, CHCl3).
IR (KBr): 3442, 2936, 1607, 1512, 1078, 842 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.0 Hz, 2 H), 6.82 (d,
J = 9.0 Hz, 2 H), 4.43 (s, 2 H), 3.78 (s, 3 H), 3.72–3.57 (m, 5 H),
3.51 (br s, 1 H), 1.83–1.74 (m, 1 H), 1.73–1.62 (m, 2 H), 0.90 (s, 9
H), 0.87 (d, J = 7.0 Hz, 3 H), 0.06 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.3, 129.1, 113.6, 74.0,
72.7, 68.0, 67.3, 55.2, 40.1, 34.5, 25.7, 18.0, 13.3, –5.6, –5.7.
MS (ESI): m/z = 369 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H37O4Si: 369.2455; found:
(2S,3R)-5-[(4-Methoxybenzyl)oxy]-2-methylpentane-1,3-diol
(11)
To a stirred suspension of CuI (19.99 g, 0.105 mol) in anhyd Et2O
(200 mL) at 0 °C was added slowly MeI (157.5 mL, 0.252 mol, 1.6
M in Et2O) under an N2 atm, and the resulting soln was stirred for
15 min at 0 °C. Epoxy alcohol 10 (10.0 g, 0.042 mol) in anhyd Et2O
(50 mL) was then added dropwise at –40 °C. Once the addition was
complete, the mixture was stirred at 0 °C for 3 h. The reaction was
quenched by the careful addition of sat. aq NH4Cl soln. The mixture
was filtered through a pad of Celite and the solid residue rinsed sev-
eral times with Et2O. The combined organic layer was washed with
brine (2 × 30 mL), dried over Na2SO4 and concentrated under re-
duced pressure to provide a 6:1 mixture of diols (10.03 g, 0.238 mol,
94%) as a pale-yellow oil. (The regioisomeric ratio was confirmed
369.2457.
tert-Butyl{[(2S,3R)-3-methoxy-5-[(4-methoxybenzyl)oxy]-2-
methylpentyl]oxy}dimethylsilane (13)
To a suspension of NaH (1.26 g, 52.7 mmol) in anhyd THF (80 mL)
was added alcohol 12 (9.8 g, 26.35 mmol) at 0 °C. After stirring for
Synthesis 2013, 45, 251–259
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Studies toward the Total Synthesis of Carolacton
255
20 min, MeI (1.96 mL, 31.63 mmol) was added slowly and stirring
was continued at r.t. for 2 h. Following completion of the reaction
(monitored by TLC), it was quenched by the dropwise addition of
ice-cold H2O. The organic layer was separated and the aq layer ex-
tracted with EtOAc (2 × 75 mL). The combined organic layer was
dried over Na2SO4 and the solvents evaporated under vacuum. The
residue was purified by column chromatography (Rf = 0.56,
EtOAc–hexane, 1:9) to afford methyl ether 13 (9.66 g, 95%) as a
colorless oil.
[α]D27 +8 (c 0.5, CHCl3).
IR (KBr): 2954, 2858, 1612, 1513, 1250, 1088, 837 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.3 Hz, 2 H), 6.81 (d,
J = 8.3 Hz, 2 H), 4.37 (ABq, J = 12.0, 1.5 Hz, 2 H), 3.79 (s, 3 H),
3.53–3.46 (m, 4 H), 3.33–3.25 (m, 4 H), 1.94–1.81 (m, 1 H), 1.80–
1.67 (m, 1 H), 1.66–1.52 (m, 1 H), 0.88 (s, 9 H), 0.85 (d, J = 6.7 Hz,
3 H), 0.03 (s, 6 H).
ture was allowed to warm to 0 °C and stirred for a further 30 min at
this temperature. The reaction was quenched with pH 7 phosphate
buffer (15 mL), MeOH (50 mL) was added, and then finally treated
with MeOH–H2O2 (2:1, 35 mL). The mixture was allowed to warm
to r.t. and stirred for 1 h. Most of the organic solvents were removed
by rotary evaporation and the aq layer was extracted with Et2O (2 ×
50 mL). The combined extracts were washed with sat. NaHCO3 soln
(2 × 10 mL) and brine (2 × 10 mL), then dried over Na2SO4, filtered,
and concentrated in vacuo. The crude residue was purified by col-
umn chromatography (Rf = 0.30, EtOAc–hexane, 3:7) to afford the
aldol product 15 (8.48 g) in 87% yield as a gummy liquid.
[α]D27 +37.0 (c 0.5, CHCl3).
IR (KBr): 3498, 2932, 1779, 1695, 1386, 1243, 1092, 757 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.15 (m, 7 H), 6.81 (d, J =
9.0 Hz, 2 H), 4.67–4.56 (m, 1 H), 4.40 (ABq, J = 11.3, 3.7 Hz, 2 H),
4.21–4.07 (m, 2 H), 3.90–3.80 (m, 1 H), 3.78 (s, 3 H), 3.71 (dd, J =
9.8, 2.2 Hz, 1 H), 3.62–3.44 (m, 3 H), 3.44–3.25 (m, 4 H), 2.72 (dd,
J = 12.8, 9.8 Hz, 1 H), 2.01–1.89 (m, 1 H), 1.88–1.73 (m, 1 H),
1.69–1.53 (m, 1 H), 1.21 (d, J = 6.7 Hz, 3 H), 0.83 (d, J = 6.7 Hz, 3
H).
13C NMR (75 MHz, CDCl3): δ = 176.8, 159.0, 152.9, 135.1, 130.4,
129.3, 129.1, 128.8, 127.2, 113.6, 80.3, 73.1, 72.5, 66.5, 66.0, 57.0,
55.3, 55.1, 39.9, 37.6, 37.1, 29.9, 10.6, 8.9.
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.6, 129.1, 113.6, 79.0,
72.5, 66.9, 64.8, 57.5, 55.1, 38.3, 30.5, 25.8, 18.2, 12.1, –5.5.
MS (ESI): m/z = 405 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H38O4NaSi: 405.2437;
found: 405.2421.
(2S,3R)-3-Methoxy-5-[(4-methoxybenzyl)oxy]-2-methylpentan-
1-ol (14)
MS (ESI): m/z = 522 [M + Na]+.
To a stirred soln of compound 13 (9.6 g, 24.6 mmol) in anhyd THF
(80 mL), TBAF (24.6 mL, 24.6 mmol, 1 M soln in THF) was added
slowly at 0 °C. After completion of the reaction as indicated by
TLC, the mixture was concentrated under reduced pressure and the
residue purified by column chromatography (Rf = 0.5, EtOAc–
hexane, 3:7) to yield the title product 14 (5.72 g, 85%) as a colorless
liquid.
[α]D27 +1 (c 0.5, CHCl3).
IR (KBr): 3436, 2927, 1612, 1513, 1247, 1089, 821 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.5 Hz, 2 H), 6.82 (d,
J = 8.5 Hz, 2 H), 4.40 (s, 2 H), 3.70 (s, 3 H), 3.63–3.45 (m, 4 H),
3.38–3.28 (m, 4 H), 2.67 (br s, 1 H), 1.92–1.65 (m, 3 H), 0.91 (d, J =
6.9 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C28H37NO7Na: 522.2467;
found: 522.2458.
(S)-4-Benzyl-3-[(2S,3R,4R,5R)-3-[(tert-butyldimethylsilyl)oxy]-
5-methoxy-7-[(4-methoxybenzyl)oxy]-2,4-dimethylheptano-
yl]oxazolidin-2-one (16)
A soln of alcohol 15 (8.4 g, 16.83 mmol) in CH2Cl2 (60 mL) was
treated with 2,6-lutidine (4.89 mL, 42.08 mmol) at 0 °C and stirred
for 20 min. Next, TBSOTf (4.25 g, 18.51 mmol) was added, and
following completion of the reaction as indicated by TLC, the mix-
ture was quenched with sat. NH4Cl soln and extracted with CH2Cl2
(3 × 50 mL). The combined organic layer was dried over anhyd
Na2SO4, and evaporated under reduced pressure to yield a viscous
liquid, which on purification by silica gel column chromatography
(Rf = 0.55, EtOAc–hexane, 1:9) afforded the silyl-protected ether 16
(10.11 g, 98%) as a colorless liquid.
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.3, 129.2, 113.7, 83.1,
72.7, 63.3, 57.9, 55.2, 38.2, 31.2, 29.6, 13.5.
MS (ESI): m/z = 291 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H24O4Na: 291.1572;
[α]D27 +21 (c 0.5, CHCl3).
IR (KBr): 2932, 2857, 1781, 1698, 1612, 1383, 1247, 1095, 835
cm–1.
found: 291.1571.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.08 (m, 7 H), 6.76 (d, J =
8.4 Hz, 2 H), 4.55–4.44 (m, 1 H), 4.35 (ABq, J = 11.5, 2.0 Hz, 2 H),
4.41–3.99 (m, 3 H), 3.75 (s, 3 H), 3.45 (t, J = 6.0 Hz, 2 H), 3.55–
3.17 (m, 6 H), 2.67 (dd, J = 13.0, 9.8 Hz, 1 H), 1.91–1.55 (m, 3 H),
1.19 (d, J = 6.9 Hz, 3 H), 0.94–0.84 (m, 12 H), 0.05 (s, 3 H), 0.04
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 176.1, 159.0, 152.8, 135.1, 130.5,
129.4, 129.1, 128.8, 127.2, 113.6, 78.7, 73.7, 72.5, 66.8, 65.8, 57.3,
55.5, 55.1, 41.4, 41.1, 37.6, 30.9, 26.0, 18.3, 13.9, 12.1, –3.8, –4.1.
(S)-4-Benzyl-3-[(2S,3R,4S,5R)-3-hydroxy-5-methoxy-7-[(4-meth-
oxybenzyl)oxy]-2,4-dimethylheptanoyl]oxazolidin-2-one (15)
A soln of (COCl)2 (2.6 mL, 29.8 mmol) in freshly distilled CH2Cl2
(40 mL) was cooled to –78 °C, and DMSO (4.22 mL, 59.6 mmol)
was carefully added under an N2 atm. After stirring for 15 min, a
soln of alcohol 14 (5.7 g, 21.2 mmol) in CH2Cl2 (20 mL) and Et3N
(12.5 mL), were added successively. The cooling bath was re-
moved, and the reaction mixture was allowed to warm to r.t. and
stirred for 2.5 h. The reaction mixture was washed with sat. aq
Na2CO3 soln (30 mL) and brine (25 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3 × 50 mL) and the combined organic layer
was dried over anhyd Na2SO4. After removal of the solvent under
reduced pressure, the crude product was used directly in the next
step. To a stirred soln of the chiral auxiliary, (S)-4-benzyl-3-propi-
onyloxazolidin-2-one (5.46 g, 23.5 mmol) in anhyd CH2Cl2 (50
mL), was added di-n-butylboryl triflate (Bu2BOTf) (23.5 mL, 23.5
mmol, 1 M in CH2Cl2) at 0 °C. The resulting brown soln was stirred
for 10 min, then Et3N (6.8 mL, 46.9 mmol) was added (the color
changed from red to light-yellow during the addition). The mixture
was stirred for 1 h at 0 °C, then cooled to –78 °C and a soln of the
above aldehyde (5.2 g, 19.5 mmol) in anhyd CH2Cl2 (15 mL) was
added. Stirring was continued for 1 h at –78 °C, and then the mix-
MS (ESI): m/z = 636 [M + Na]+.
(2R,3S,4R,5R)-3-[(tert-Butyldimethylsilyl)oxy]-5-methoxy-7-
[(4-methoxybenzyl)oxy]-2,4-dimethylheptan-1-ol (17)
The procedure was identical to that described for the preparation of
alcohol 6 (see below). The TBS ether 16 (10 g, 16.31) in MeOH (10
mL) was treated with LiBH4 (24.4 mL, 48.8 mmol, 2.0 M soln in
THF) to give, after work-up, the alcohol 17 (6.46 g, 90%) as a col-
orless liquid (Rf = 0.45, EtOAc–hexane, 3:7).
[α]D27 +1.0 (c 0.5, CHCl3).
IR (KBr): 3451, 2955, 2931, 2857, 1612, 1513, 1465, 1249, 1090,
1035, 835, 772 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 251–259

256
G. Sabitha et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.21 (d, J = 9.0 Hz, 2 H), 6.82 (d,
J = 9.0 Hz, 2 H), 4.40 (ABq, J = 12.1, 1.2 Hz, 2 H), 3.88–3.76 (m,
4 H), 3.57–3.35 (m, 5 H), 3.28 (s, 3 H), 2.04–1.58 (m, 4 H), 1.49–
1.39 (br s, 1 H), 0.93–0.82 (m, 15 H), 0.07 (s, 3 H), 0.05 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.5, 129.2, 113.6, 79.0,
72.9, 72.6, 66.8, 66.2, 56.4, 55.1, 40.4, 38.3, 30.4, 26.0, 18.2, 11.7,
11.5, –4.0, –4.2.
[α]D27 +15.0 (c 0.5, CHCl3).
IR (KBr): 2932, 1606, 1512, 1251, 1092, 829 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.3 Hz, 2 H), 6.80 (d,
J = 8.5 Hz, 2 H), 4.39 (ABq, J = 11.3, 3.7 Hz, 2 H), 3.79 (s, 3 H),
3.67–3.58 (m, 2 H), 3.50 (dd, J = 6.7, 5.2 Hz, 2 H), 3.28 (s, 3 H),
2.61–2.47 (m, 1 H), 2.09–1.94 (m, 1 H), 1.90–1.78 (m, 1 H), 1.73
(d, J = 2.2 Hz, 3 H), 1.60–1.45 (m, 1 H), 1.10 (d, J = 6.7 Hz, 3 H),
0.89 (s, 9 H), 0.84 (d, J = 6.7 Hz, 3 H), 0.09 (s, 3 H), 0.06 (s, 3 H).
MS (ESI): m/z = 463 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H24O4Na: 463.2855;
found: 463.2851.
13C NMR (75 MHz, CDCl3): δ = 159.0, 130.8, 129.1, 113.6, 96.1,
83.0, 78.4, 76.9, 72.5, 66.9, 57.0, 55.0, 40.4, 31.0, 29.7, 26.2, 18.4,
17.4, 11.1, 3.6, –3.8, –3.9.
MS (ESI): m/z = 471 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H44O4SiNa: 471.2906;
tert-Butyl{[(3R,4S,5R,6R)-1,1-dibromo-6-methoxy-8-[(4-meth-
oxybenzyl)oxy]-3,5-dimethyloct-1-en-4-yl]oxy}dimethylsilane
(18)
A soln of alcohol 17 (6.4 g, 14.54 mmol) in anhyd CH2Cl2 (25 mL)
was added to a suspension of Dess–Martin periodinane (7.4 g, 17.45
mmol) and NaHCO3 (3.7 g, 34.90 mmol) in CH2Cl2 (25 mL) at 0 °C,
and the mixture stirred at the same temperature for 1 h. After com-
pletion of the reaction as indicated by TLC, the mixture was diluted
with CH2Cl2 (25 mL) and washed with sat. aq NaHCO3 soln (2 × 20
mL) and sat. aq Na2S2O3 soln (2 × 20 mL). The organic layer was
dried over Na2SO4, evaporated in vacuo, and purification by silica
gel column chromatography (Rf = 0.30, EtOAc–hexane, 1:9) afford-
ed the corresponding aldehyde (5.4 g, 85%) as a colorless oil, which
was used directly in the next step. To a soln of Ph3P (12.92 g, 49.31
mmol) in anhyd CH2Cl2 (75 mL) at –10 °C was added CBr4 (8.23 g,
24.64 mmol) in portions. The mixture was stirred for 15 min before
Et3N (3.66 mL, 24.64 mmol) followed by the intermediate aldehyde
(5.4 g, 12.32 mmol) were added in CH2Cl2 (30 mL + 15 mL) via
cannula. After completion of the reaction as indicated by TLC, the
mixture was quenched with sat. aq NaHCO3 soln and extracted with
CH2Cl2 (3 × 50 mL). The combined organic layer was dried over an-
hyd Na2SO4 and evaporated under reduced pressure. The residue
was purified by silica gel column chromatography (Rf = 0.40,
EtOAc–hexane, 1:19) to afford the dibromoalkene 18 (6.81 g, 93%)
as a colorless liquid.
found: 471.2908.
tert-Butyl{[(4R,5S,6R,7R,1E)-2-iodo-7-methoxy-9-[(4-methoxy-
benzyl)oxy]-4,6-dimethylnon-2-en-5-yl]oxy}dimethylsilane (4)
To a stirred soln of ZrCp2Cl2 (3.2 g, 11.0 mmol) in THF (20 mL) at
0 °C was added dropwise DIBAL-H (6.5 mL, 11.0 mmol, 1.7 M
soln in toluene). The resulting suspension was stirred for 30 min at
the same temperature followed by addition of a soln of alkyne 19
(4.5 g, 10.0 mmol) in THF (30.0 mL). The mixture was warmed to
r.t. and stirred until a homogeneous soln resulted, which was cooled
to –78 °C and treated with I2 (3.30 g, 13.1 mmol) in THF (15 mL).
After 30 min at –78 °C, the mixture was quenched with HCl (1 M),
extracted with Et2O (3 × 50 mL), and the organic layer washed suc-
cessively with sat. aq Na2S2O3 soln (2 × 10 mL), sat. aq NaHCO3
soln (2 × 10 mL) and brine (2 × 10 mL), dried over Na2SO4, and
concentrated under reduced pressure. The crude residue was sub-
jected to silica gel column chromatography (Rf = 0.60, EtOAc–
hexane, 1:19) to furnish the desired iodoalkene 4 (5.09 g) in 88%
yield as a colorless liquid.
[α]D27 +26.0 (c 0.5, CHCl3).
IR (KBr): 2937, 2859, 1613, 1512, 1249, 1093, 835 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.26 (d, J = 8.3 Hz, 2 H), 6.87 (d,
J = 8.4 Hz, 2 H), 6.06 (d, J = 10.0 Hz, 1 H), 4.40 (ABq, J = 11.5, 3.5
Hz, 2 H), 3.80 (s, 3 H), 3.62–3.46 (m, 3 H), 3.42–3.22 (m, 4 H),
2.68–2.49 (m, 1 H), 2.36 (s, 3 H), 1.99–1.53 (m, 3 H), 0.96 (d, J =
6.6 Hz, 3 H), 1.91 (s, 9 H), 0.84 (d, J = 7.1 Hz, 3 H), 0.07 (s, 3 H),
0.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 145.4, 130.6, 129.4, 113.6,
93.1, 78.4, 76.0, 72.6, 66.6, 56.5, 55.2, 40.3, 38.6, 30.3, 29.6, 27.6,
26.1, 18.3, 16.0, 11.2, –3.8, –3.9.
[α]D27 –2.0 (c 0.5, CHCl3).
IR (KBr): 2936, 2858, 1613, 1512, 1249, 1091, 834, 778 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.3 Hz, 2 H), 6.81 (d,
J = 8.3 Hz, 2 H), 6.30 (d, J = 9.0 Hz, 1 H), 4.39 (ABq, J = 11.3, 2.2
Hz, 2 H), 3.90 (s, 3 H), 3.70 (t, J = 5.2 Hz, 1 H), 3.49 (t, J = 6.7 Hz,
1 H), 3.35–3.23 (m, 5 H), 2.68–2.51 (m, 1 H), 1.98–1.74 (m, 2 H),
1.79–1.52 (m, 1 H), 1.00 (d, J = 6.7 Hz, 3 H), 0.89 (s, 9 H), 0.86 (d,
J = 7.5 Hz, 3 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 143.0, 130.6, 129.2, 113.6,
87.4, 78.5, 74.5, 72.6, 66.7, 56.5, 55.2, 41.0, 40.5, 30.1, 26.0, 18.3,
14.0, 10.7, –3.9, –4.0.
MS (ESI): m/z = 599 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H45IO4SiNa: 599.2029;
found: 599.2013.
MS (ESI): m/z = 615 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H42O4Br2NaSi: 615.1111;
found: 615.1116.
(R)-2,2-Dimethyl-3-(3-methylpent-4-en-1-yl)oxirane (20)
To a stirred suspension of (–)-β-citronellene (8) (10 g, 72.4 mmol)
and NaOAc (6.23 g, 76.0 mmol) in CH2Cl2 (250 mL) was added
portionwise MCPBA (12.46 g, 72.4 mmol) at –20 °C over a period
of 0.5 h. After complete consumption of the starting material as in-
dicated by TLC, the mixture was filtered through a plug of Celite.
Sat. aq NaHCO3 soln (100 mL) was added to the filtrate at 0 °C,
which was then stirred for 1 h. The aq layer was extracted with
CH2Cl2 (2 × 100 mL) and the combined organic layer washed with
brine (2 × 30 mL) followed by H2O (2 × 50 mL), and then dried over
Na2SO4. Concentration under reduced pressure and column chro-
matography of the residue on silica gel (Rf = 0.30, EtOAc–hexane,
1:9) gave oxirane 20 (9.48 g, 85%) as a colorless oil.
tert-Butyl{[(4R,5S,6R,7R)-7-methoxy-9-[(4-methoxyben-
zyl)oxy]-4,6-dimethylnon-2-yn-5-yl]oxy}dimethylsilane (19)
To a cooled (–78 °C) soln of dibromoalkene 18 (6.4 g, 10.7 mmol)
in THF (50 mL) was added n-BuLi (10.7 mL, 26.9 mmol, 2.5 M in
hexanes) over 1 h. After the addition was complete, the mixture was
allowed to warm to –25 °C and stirred at this temperature for 1 h.
The mixture was again cooled to –78 °C and MeI (2 mL, 32.3
mmol) was added dropwise. After 1 h, the soln was quenched with
sat. aq NH4Cl soln (20 mL). The aq layer was separated and extract-
ed with Et2O (3 × 50 mL). The combined organic layer was washed
with brine (20 mL), dried over Na2SO4 and concentrated in vacuo.
Purification by column chromatography on silica gel (Rf = 0.70,
EtOAc–hexane, 1:9) afforded methylated alkyne 19 (4.53 g) in 94%
yield as a colorless liquid.
IR (KBr): 3065, 2865, 1642, 1125, 1009, 920 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.73–5.56 (m, 1 H), 5.00–4.88 (m,
2 H), 2.65–2.58 (m, 1 H), 2.44–2.07 (m, 1 H), 1.57–1.30 (m, 4 H),
1.28 (s, 3 H), 1.24 (s, 3 H), 1.02 (d, J = 6.6 Hz, 3 H).
Synthesis 2013, 45, 251–259
© Georg Thieme Verlag Stuttgart · New York

PAPER
Studies toward the Total Synthesis of Carolacton
257
13C NMR (75 MHz, CDCl3): δ (mixture of diastereomers) = 143.9,
143.8, 112.9, 112.8, 64.5, 64.3, 58.3, 58.2, 37.6, 37.4, 33.1, 33.0,
26.5, 26.4, 24.6 (2 C), 20.1, 19.9.
(Rf = 0.35, EtOAc–hexane, 3:7) gave the pure acid 23 (4.68g, 85%)
as a colorless oil.
[α]D27 +3.0 (c 0.5, CHCl3).
IR (KBr): 3445, 2932, 2865, 1710, 1641, 1415, 911, 679 cm–1.
MS (ESI): m/z = 177 [M + Na]+.
(R,E)-Ethyl 6-Methylocta-2,7-dienoate (21)
1H NMR (300 MHz, CDCl3): δ = 5.70–5.55 (m, 1 H), 4.93 (d, J =
16.6 Hz, 1 H), 4.88 (d, J = 8.3 Hz, 1 H), 2.33 (t, J = 7.5 Hz, 2 H),
2.17–2.00 (m, 1 H), 1.69–1.55 (m, 2 H), 1.39–1.24 (m, 4 H), 0.99
(d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 180.4, 144.4, 112.6, 37.6, 36.2,
34.1, 26.7, 24.1, 2.2.
To a soln of H5IO6 (16.7 g, 73.24 mmol) in THF–H2O (60 mL, 5:1)
was added a soln of epoxide 20 (9.4 g, 61.03 mmol) in THF (15 mL)
at 0 °C. The mixture was stirred for 15 min at the same temperature.
After total consumption of the starting material as indicated by
TLC, Et2O (20 mL) was added and the organic layer was separated.
The aq layer was extracted with Et2O (3 × 100 mL), and the com-
bined organic layer washed with sat. aq NaHCO3 soln (50 mL) and
brine (30 mL), and then dried over Na2SO4. The crude aldehyde was
used directly in the next step. To a soln of the aldehyde in CH2Cl2
(100 mL) was added Ph3P=CHCO2Et (23.4 g, 67.5 mmol) and the
resulting mixture stirred at r.t. for 30 min. The mixture was diluted
with CH2Cl2 (80 mL) and washed with brine (30 mL) and H2O (30
mL). The organic layer was dried over anhyd Na2SO4 and concen-
trated under vacuum. The crude residue was purified by silica gel
column chromatography (Rf = 0.60, EtOAc–hexane, 1:19) to afford
the pure ester 21 (8.1 g, 73% over two steps) as a colorless oil.
MS (ESI): m/z = 179 [M + Na]+.
(S)-4-Benzyl-3-[(R)-6-methyloct-7-enoyl]oxazolidin-2-one (24)
To a stirred soln of acid 23 (4 g, 25.6 mmol) in anhyd THF (80 mL)
at –20 °C was added Et3N (9.0 mL, 64.1 mmol) followed by PivCl
(3.19 mL, 25.6 mmol). After stirring for 1 h at –20 °C, LiCl (1.78 g,
42.05 mmol) and (S)-4-benzyloxazolidin-2-one (4.5 g, 25.6 mmol)
were added at the same temperature. Stirring was continued for 1 h
at –20 °C and then for 2 h at 0 °C. The mixture was quenched with
sat. aq NH4Cl soln (50 mL) and extracted with EtOAc (2 × 80 mL).
The combined organic layer was washed with brine (30 mL), dried
over anhyd Na2SO4 and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography
(Rf = 0.34, EtOAc–hexane, 1:18) to give the title product 24 (7.67
g, 95%) as a colorless gummy liquid.
[α]D27 +50 (c 0.5, CHCl3).
IR (KBr): 2927, 2862, 1782, 1700, 1453, 1386, 1207, 703 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.16 (m, 5 H), 5.57–5.59 (m,
1 H), 4.95 (d, J = 17.3 Hz, 1 H), 4.90 (d, J = 9.8 Hz, 1 H), 4.70–4.61
(m, 1 H), 4.23–4.11 (m, 2 H), 3.29 (dd, J = 13.5, 3.0 Hz, 1 H), 3.03–
2.70 (m, 3 H), 2.19–2.04 (m, 1 H), 1.74–1.61 (m, 2 H), 1.43–1.27
(m, 4 H), 0.99 (d, J = 6.7 Hz, 3 H).
[α]D27 –2.0 (c 0.5, CHCl3).
IR (KBr): 2966, 2932, 1721, 1653, 1455, 1271, 1181, 680 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.99–6.84 (m, 1 H), 5.77 (d, J =
15.8 Hz, 1 H), 5.71–5.54 (m, 1 H), 4.97 (d, J = 10.5 Hz, 1 H), 4.93
(d, J = 3.0 Hz, 1 H), 4.16 (q, J = 6.7 Hz, 2 H), 2.25–2.08 (m, 3 H),
1.46 (q, J = 7.5 Hz, 2 H), 1.29 (t, J = 7.5 Hz, 3 H), 1.01 (d, J = 6.7
Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 166.6, 149.1, 143.7, 121.2, 113.2,
60.0, 37.2, 34.6, 29.8, 20.1, 14.2.
MS (ESI): m/z = 200 [M + NH4]+.
(R)-Methyl 6-Methyloct-7-enoate (22)
13C NMR (75 MHz, CDCl3): δ = 173.2, 153.3, 144.5, 135.2, 129.3,
128.3, 127.2, 112.4, 66.0, 55.0, 37.8, 37.5, 36.2, 35.4, 26.7, 24.2,
20.1.
MS (ESI): m/z = 338 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H25NO3Na: 338.1732;
To a stirred soln (8.0 g, 43.9 mmol) of ethyl ester 21 in anhyd
MeOH (150 mL) was added Mg granules (2.6 g, 109 mmol) under
an N2 atm. After a 30 min induction period, a mild exothermic reac-
tion started with evolution of H2 gas. Stirring was continued for 2 h
to dissolve the Mg completely, whilst maintaining the reaction tem-
perature at 10 °C using an ice-bath. The mixture was poured into
ice-cold HCl (100 mL, 3 M) and stirred vigorously to give a clear
soln. This acidic soln was treated with NH4OH soln (3 M) until pH
8.5–9.0, and then extracted with Et2O (2 × 100 mL). The combined
organic layer was washed with brine (40 mL), dried over Na2SO4,
and concentrated in vacuo. Purification over silica gel (Rf = 0.60,
EtOAc–hexane, 1:19) gave (R)-methyl 6-methyloct-7-enoate (22)
(6.72 g, 90%) as a colorless oil.
found: 338.1746.
(S)-4-Benzyl-3-[(2S,6R)-2,6-dimethyloct-7-enoyl]oxazolidin-2-
one (25)
To a stirred soln of 24 (4.05 g, 12.8 mmol) in anhyd THF (50 mL)
at –78 °C was slowly added dropwise NaHMDS (19.3 mL, 19.3
mmol, 1 M soln in THF) with stirring under an N2 atm. After stirring
for 30 min at the same temperature, MeI (2.4 mL, 38.5 mmol) was
added dropwise and stirring was continued for another 2 h. The mix-
ture was quenched with sat. aq NH4Cl soln (50 mL), warmed to r.t.
and extracted with EtOAc (2 × 100 mL). The combined organic ex-
tract was washed with brine (50 mL), dried over anhyd Na2SO4 and
concentrated in vacuo. The crude residue was purified by silica gel
column chromatography (Rf = 0.37, EtOAc–hexane, 2:18) to afford
the methylated product 25 (3.89 g, 92%) as a colorless viscous liq-
uid.
[α]D27 +12.0 (c 0.5, CHCl3)
IR (KBr): 2929, 2865, 1737, 1459, 1375, 1171, 912 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.74–5.60 (m, 1 H), 4.95 (d, J =
15.2 Hz, 1 H), 4.90 (d, J = 10.2 Hz, 1 H), 3.66 (s, 3 H), 2.31 (t, J =
7.5 Hz, 2 H), 2.18–2.03 (m, 1 H), 1.68–1.52 (m, 2 H), 1.35–1.22 (m,
4 H), 0.98 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 174.2, 144.6, 112.5, 51.4, 37.5,
36.2, 34.1, 26.7, 25.0, 20.2.
MS (ESI): m/z = 193 [M + Na]+.
[α]D27 +51.0 (c 0.5, CHCl3).
IR (KBr): 2929, 2862, 1781, 1697, 1455, 1385, 1212, 701 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.16 (m, 5 H), 5.72–5.53 (m,
1 H), 4.92 (d, J = 15.8 Hz, 1 H), 4.88 (d, J = 8.3 Hz, 1 H), 4.67–4.57
(m, 1 H), 4.23–4.07 (m, 2 H), 3.72–3.59 (m, 1 H), 3.28 (dd, J = 13.5,
3.0 Hz, 1 H), 2.72 (d, J = 9.8 Hz, 0.5 H), 2.68 (d, J = 10.5 Hz, 0.5
H), 2.17–2.05 (m, 1 H), 1.79–1.62 (m, 1 H), 1.47–1.24 (m, 5 H),
1.20 (d, J = 6.7 Hz, 3 H), 0.98 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 177.1, 152.9, 144.5, 135.2, 129.3,
128.8, 127.2, 112.4, 65.9, 55.2, 37.7, 37.6, 37.5, 36.3, 33.2, 24.7,
20.1, 17.2.
(R)-6-Methyloct-7-enoic Acid (23)
LiOH·H2O (4.44 g, 105.8 mmol) was added portionwise to a cooled
soln (0 °C) of ester 22 (6.0 g, 35.29 mmol) in THF–MeOH–H2O (80
mL, 4:1:1) and the mixture stirred for 2 h at r.t. The mixture was
concentrated in vacuo, and the residue diluted with THF (40 mL)
and washed with HCl (2 M, 20 mL) and then the aqueous layer was
extracted with EtOAc (3 × 50 mL). The combined organic layer was
washed with brine (2 × 20 mL), dried over Na2SO4 and concentrated
under reduced pressure. Column chromatography of the residue
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 251–259

258
G. Sabitha et al.
PAPER
MS (ESI): m/z = 352 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H27NO3Na: 352.1888;
chromatography (Rf = 0.35, EtOAc–hexane, 3:7) to give pure cross-
metathesis product 27 (0.57 g, 75%) as a colorless liquid.
[α]D27 –53.3 (c 1.0, CHCl3).
found: 352.1885.
IR (KBr): 3426, 2926, 2862, 1756, 1633, 1380, 1207, 1096, 879
cm–1.
(2S,6R)-2,6-Dimethyloct-7-en-1-ol (6)
Anhyd MeOH (1.4 mL, 34.6 mmol) and LiBH4 (17.3 mL, 34.65
mmol, 2.0 M soln in THF) were added to a stirred soln of 25 (3.8 g,
11.55 mmol) in THF (40 mL) at 0 °C. The resulting mixture was
stirred at the same temperature for 45 min. After completion of the
reaction (monitored by TLC), the mixture was quenched with aq
NaOH soln (50 mL, 1.0 M). The phases were filtered over a pad of
Celite and separated. The aq phase was extracted with CH2Cl2 (3 ×
50 mL) and the combined organic layer washed with brine (20 mL),
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (Rf =
0.50, EtOAc–hexane, 2:8) to yield alcohol 6 (1.62 g, 90%) as a col-
orless liquid.
1H NMR (500 MHz, CDCl3): δ = 5.68 (dd, J = 15.0, 7.0 Hz, 1 H),
5.24 (dd, J = 16.0, 8.0 Hz, 1 H), 4.71 (t, J = 8.0 Hz, 1 H), 4.57 (d,
J = 7.0 Hz, 1 H), 3.69 (s, 3 H), 3.48–3.37 (m, 2 H), 2.19–2.10 (m, 1
H), 1.63–1.54 (m, 4 H), 1.37 (s, 3 H), 1.34–1.22 (m, 5 H), 1.16–1.03
(m, 1 H), 0.97 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.0, 142.6, 122.0, 110.8, 78.8,
77.7, 68.0, 51.6, 36.6, 36.1, 35.5, 33.0, 26.8, 25.4, 24.3, 20.0, 16.5.
MS (ESI): m/z = 337 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C17H30O5Na: 337.1990;
found: 337.1991.
[α]D27 –13.4 (c 1.0, CHCl3).
IR (KBr): 3420, 2925, 2859, 1641, 1455, 1034 cm–1.
(4R,5R)-Methyl 5-[(3R,7S,E)-3,7-Dimethyl-8-oxooct-1-en-1-yl]-
2,2-dimethyl-1,3-dioxolane-4-carboxylate (3)
1H NMR (500 MHz, CDCl3): δ = 5.72–5.61 (m, 1 H), 4.94 (d, J =
17.8 Hz, 1 H), 4.89 (d, J = 9.8 Hz, 1 H), 3.49 (dd, J = 9.8, 5.9 Hz, 1
H), 3.41 (dd, J = 10.8, 6.9 Hz, 1 H), 2.14–2.07 (m, 1 H), 1.65–1.55
(m, 1 H), 1.44–1.17 (m, 5 H), 1.14–1.03 (m, 1 H), 0.98 (d, J = 6.9
Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 144.7, 112.5, 68.1, 37.6, 36.7, 35.6,
33.0, 24.4, 20.1, 16.4.
The same oxidation procedure as that described for the preparation
of the aldehyde precursor to compound 18 was employed. The alco-
hol 27 (100 mg, 0.31 mmol) was treated with Dess–Martin perio-
dinane (162 mg, 0.38 mmol) in the presence of NaHCO3 (81 mg,
0.76 mmol) to furnish after work-up and purification, the aldehyde
3 (84 mg, 85%) as a colorless liquid.
[α]D27 –110.0 (c 0.15, CHCl3).
IR (KBr): 2928, 2861, 1732, 1455, 1375, 1208, 1093, 878 cm–1.
MS (ESI): m/z = 179 [M + Na]+.
1H NMR (300 MHz, CDCl3): δ = 9.58 (s, 1 H), 5.67 (dd, J = 15.0,
7.0 Hz, 1 H), 5.24 (dd, J = 15.0, 7.0 Hz, 1 H), 4.71 (t, J = 7.0 Hz, 1
H), 4.57 (d, J = 7.0 Hz, 1 H), 3.68 (s, 3 H), 2.34–2.24 (m, 1 H), 2.20–
2.10 (m, 1 H), 1.76–1.63 (m, 1 H), 1.60 (s, 3 H), 1.38 (s, 3 H), 1.35–
1.27 (m, 5 H), 1.09 (d, J = 7.0 Hz, 3 H), 0.97 (d, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 205.1, 170.0, 142.3, 122.5, 111.0,
78.8, 77.8, 51.7, 46.2, 36.4, 36.1, 30.5, 26.9, 25.5, 24.4, 20.0, 13.3.
(4R,5R)-Methyl 2,2-Dimethyl-5-ethenyl-1,3-dioxolane-4-car-
boxylate (5)
To a stirred soln of aldehyde 26 (1.2 g, 7.69 mmol) in t-BuOH (20
mL) was added 2-methyl-2-butene (9.0 mL, 9.0 mmol, 1 M soln in
THF) at r.t. NaH2PO4 (2.78 g, 18.1 mmol) and NaClO2 (1.04 g, 11.5
mmol) were dissolved in H2O (10 mL) to give a clear soln, which
was subsequently added to the reaction mixture at 0 °C. The mixture
was allowed to stir for a further 1 h at r.t., and then was diluted with
H2O (15 mL). The organic solvent was removed under reduced
pressure and the aq layer extracted with EtOAc (3 × 50 mL). The
combined organic layer was washed with brine (2 × 50 mL), dried
over anhyd Na2SO4 and evaporated under reduced pressure. The
crude residue was purified by silica gel column chromatography
(EtOAc–hexane, 2:5) to afford the corresponding acid (1.12 g,
85%) as a colorless oil. This acid (1.12 g, 6.51 mmol) was dissolved
in Et2O (2 mL) and treated with freshly prepared diazomethane in
Et2O. After stirring for 1 h, the solvent was evaporated at low water-
bath temperature and the residue was purified by column chroma-
tography on silica gel (Rf = 0.35, EtOAc–hexane, 1:9) to furnish the
ester 5 in 95% yield as a colorless liquid. CAUTION: potentially
explosive.
MS (ESI): m/z = 335 [M + Na]+.
(4R,5R)-Methyl 5-{(1E,3R,7S,9E,11R,12S,13R,14R)-12-[(tert-
Butyldimethylsilyl)oxy]-8-hydroxy-14-methoxy-16-[(4-meth-
oxybenzyl)oxy]-3,7,9,11,13-pentamethylhexadeca-1,9-dienyl}-
2,2-dimethyl-1,3-dioxalone-4-carboxylate (2)
To a dry, two-necked, round-bottomed flask (25 mL) equipped with
a magnetic stir bar and septum were added anhyd CrCl2 (196 mg,
1.6 mmol) and a trace amount of anhyd NiCl2 under an Ar atm. An-
hyd DMSO (2.0 mL) was added and the resulting suspension stirred
at r.t. for 10 min. Aldehyde 3 (50 mg, 0.16 mmol) dissolved in an-
hyd DMSO (1.0 mL) was added to the mixture, which was stirred
for a further 10 min. Next, iodide 4 (276 mg, 0.48 mmol) in anhyd
DMSO (1 mL) was added and stirring was continued for 10 h. After
completion of the reaction, the mixture was diluted with Et2O and
quenched with aq NH4Cl soln. The reaction mixture was extracted
with Et2O (2 × 10 mL) and the combined organic layer dried over
anhyd Na2SO4 and concentrated under reduced pressure. The resi-
due was purified by silica gel column chromatography (Rf = 0.30,
EtOAc–hexane, 2:8) to furnish the pure title product 2 (6:4 mixture
of epimers, 38 mg, 31%) as a colorless viscous liquid.
[α]D27 –47.0 (c 0.5, CHCl3).
IR (KBr): 2925, 1735, 1629, 1394, 1024, 754 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.77–5.61 (m, 1 H), 5.39 (d, J =
16.9 Hz, 1 H), 5.27 (d, J = 10.0 Hz, 1 H), 4.75 (t, J = 6.9 Hz, 1 H),
4.61 (d, J = 7.1 Hz, 1 H), 3.69 (s, 3 H), 1.61 (s, 3 H), 1.38 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 169.6, 131.9, 118.9, 110.9, 78.4,
77.5, 51.4, 26.6, 25.3.
MS (ESI): m/z = 186 [M]+.
IR (KBr): 3454, 2929, 2857, 1759, 1613, 1512, 1460, 1375, 1249,
1204, 1094, 1035, 834 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.24 (d, J = 7.5 Hz, 2 H), 6.85 (d,
J = 8.3 Hz, 2 H), 5.72 (dd, J = 15.1, 7.5 Hz, 1 H), 5.35–5.17 (m, 2
H), 4.75 (t, J = 7.5 Hz, 1 H), 4.61 (d, J = 6.8 Hz, 1 H), 4.41 (ABq,
J = 12.0, 1.8 Hz, 2 H), 3.81–3.74 (m, 4 H), 3.69 (s, 3 H), 3.60–3.38
(m, 4 H), 3.25 (s, 3 H), 2.67–2.50 (m, 1 H), 2.20–2.07 (m, 1 H),
1.95–1.64 (m, 3 H), 1.63–1.58 (m, 4 H), 1.56 (s, 3 H), 1.38 (s, 3 H),
1.34–1.18 (m, 6 H), 0.97–0.80 (m, 21 H), 0.05 (s, 3 H), 0.04 (s, 3 H).
(4R,5R)-Methyl 5-[(3R,7S,E)-8-Hydroxy-3,7-dimethyloct-1-en-
1-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate (27)
A mixture of terminal alkene 6 (0.452 g, 2.9 mmol), alkene 5 (0.45
g, 2.41 mmol) and Grubbs’ II catalyst (10 mol%) in CH2Cl2 (5 mL)
was stirred at 27 °C under an N2 atm for 10 h. After completion of
the reaction as indicated by TLC, the mixture was concentrated un-
der reduced pressure and the residue subjected to silica gel column
MS (ESI): m/z = 786 [M + Na]+.
Synthesis 2013, 45, 251–259
© Georg Thieme Verlag Stuttgart · New York

PAPER
Studies toward the Total Synthesis of Carolacton
259
HRMS (ESI): m/z [M + Na]+ calcd for C43H74O9NaSi: 785.4999;
found: 785.4990.
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Acknowledgment
K.S. and M.N.P. thank the CSIR, New Delhi, India, for the award
of fellowships.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 251–259